Allosteric Inhibition of [125I] ET-1 Binding to ETA Receptors by Salicylic Acid Dimers

Original Article


Musa Ahmed ¹, Susanna Nencetti ², Maria R. Mazzoni ³,Francesca Porchia ³, Federica Antonelli ², Annalina Lapucci ²

1-Department of Pharmaceutical Chemistry, Garyounis University, Benghazi, Libya 2-Department of Pharmaceutical Science, University of Pisa, Italy. 3-Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Italy.

JMJ 2009,Vol.9, No.1: 46-50


Endothelin-1 (ET-1), a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ETA and ETB. An unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid (SA) are allosteric inhibitors of ET-1 binding to ETA receptors. Dihalgenated derivatives of (SA) have been identified as more potent allosteric inhibitors than aspirin. In this study, dihalo-salicylic acid dimers were synthesized and tested as inhibitors of [125 I] ET-1 binding to ETA receptors in rat embryonic cardiomyocyte (H9c2 cell) membranes in aim to develop of new potential allosteric inhibitors of ET-1. Some dihalo- salicylic acid dimers synthesized in this study showed promising activity as inhibitors of [125I] ET-1 binding to ETA receptors in comparison with the dihalosalicylic acid reported in literature, the bromo substituted compound B showed very interesting activity more than other halogen substituted dimers, it caused about 40% inhibition at 100µ M and caused 100% inhibition at 500µ M. We conclude that dihalo- salicylic acid dimers can mediate good inhibition activity in comparison to sole dihalo- salicylic acid molecules.

Keywords: Allosteric, Endothelin-1, 3, 5-Diiodosalicylic acid, ETA receptors, Bis (3, 5-diiodiosalicyl) Succinate, bis (3,5-dibromosalicyl) Succinate, Bis (3, 5-dichlorosalicyl) Succinate.